Rituximab anti-CD20 IgG therapy is credited with revitalizing antibody therapies with its ability to effectively treat follicular lymphoma without the extensive side effects associated with more traditional chemotherapy regimens. Since rituximab's approval by the FDA in 1997, the mortality rate from NHL has declined by 2.8% per year (Molina, 2008, Ann Rev Med 59:237-50), and the use of this agent has been expanded to a variety of diseases. While rituximab has been a remarkable success in follicular non-Hodgkin lymphoma (NHL), for which it was first approved, only half of the patients had an objective response, with at most 10% having a complete response (McLaughlin et al., 1998, J Clin Oncol 16:2825-33). Rituximab was less effective in the more aggressive types of NHL, such as diffuse large B cell lymphoma (DLBCL), but when it was combined with combination chemotherapy, improved and durable objective responses compared to the separate therapies were found, making R-CHOP a standard protocol for the treatment of DLBCL (e.g., Leonard et al., 2008, Semin Hematol 45:S11-16; Friedberg et al., 2002, Br J Haematol 117:828-34). The success of rituximab stimulated the evaluation of a number of other antibodies and antibody conjugates, and while a number of these have shown promising activity, to-date only one other unconjugated antibody therapy, alemtuzumab anti-CD52 for chronic lymphocytic leukemia (CLL), has been approved for use in hematologic malignancies (Robak, 2008, Curr Cancer Drug Targets 8:156-71).
Novel immunotherapeutic approaches, such as infusion of monoclonal antibodies (mAbs) to improve the management of lymphoma, are traditionally examined in murine models for efficacy and in Cynomolgus monkeys for safety and pharmacodynamics/pharmacokinetics, but could be more carefully evaluated prior to human studies to identify and better anticipate the impact of such interventions in humans if other tumor models were available. Spontaneously-arising neoplasms in companion animals have been proposed as a useful system for examining numerous hypotheses relevant to human cancer control, and have recently been acknowledged by the National Cancer Institute as valuable study models (Dewhirst et al., 2001, Spontaneous Pet Animal Cancers. In: B. A. Teicher (ed.), Tumor Models in Cancer Research., pp. 565-89. Totowa, N.J.: Humana Press; Hansen and Khanna, 2004, Eur J Can 40:858-80; Paloni and Khanna, 2008, Nature Reviews Cancer 8:147-56). Canine lymphoma is particularly valuable as a model system, because it is common (incidence 25-40/100,000), similar pathologically to human high-grade, B cell NHL, and is initially controllable with chemotherapy followed by subsequent resistance that limits long-term control (median remission and survival times are 6-9 months and 10-14 months, respectively) (Vail and Young, 2007, Canine lymphoma and lymphoid leukemia. In: S. J. Withrow and D. M. Vail (eds.), Small Animal Clinical Oncology., 4 edition, pp. 699-733. St. Louis (MO): Saunders). Recent investigations have confirmed that canine lymphoma is genetically similar to the human disease (Modiano et al., 2005, Cancer Res 65:5654-61; Breen and Modiano, 2008, Croimosome Res 16:145-54), further justifying the model for evaluating novel, targeted therapeutic strategies for the benefit of both species.
The human leukocyte antigen-DR (HLA-DR) is one of three isotypes of the major histocompatibilty complex (MHC) class II antigens. HLA-DR is highly expressed on a variety of hematologic malignancies and has been actively pursued for antibody-based lymphoma therapy (Brown et al., 2001, Clin Lymphoma 2:188-90; DeNardo et al., 2005, Clin Cancer Res 11:7075s-9s; Stein et al., 2006, Blood 108:2736-44). Preliminary studies indicate that anti-HLA-DR mAbs are markedly more potent than other naked mAbs of current clinical interest in in vitro and in vivo experiments in lymphomas, leukemias, and multiple myeloma (Stein et al., unpublished results). HLA-DR is also expressed on a subset of normal immune cells, including B cells, monocytes/macrophages, Langerhans cells, dendritic cells, and activated T cells (Dechant et al., 2003, Semin Oncol 30:465-75). Thus, it is perhaps not surprising that infusional toxicities, likely related to complement activation, have been problematic clinically with the administration of anti-HLA-DR antibody (Shi et al., 2002, Leuk Lymphoma 43:1303-12.
The L243 antibody (hereafter mL243) is a murine IgG2an anti-HLA-DR antibody. This antibody may be of potential use in the treatment of diseases such as autoimmune disease or cancer, particularly leukemias or lymphomas, by targeting the D region of HLA. mL243 demonstrates potent suppression of in vitro immune function and is monomorphic for all HLA-DR proteins. However, problems exist with the administration of mouse antibodies to human patients, such as the induction of a human anti-mouse antibody (HAMA) response. A need exists for antibodies with the antigenic specificity of mL243, that may be administered to human subjects.